Use of agonists of adrenergic β-3 receptors for preparing wound-healing medicines

ABSTRACT

The invention relates to the use of β 3 -adrenergic receptor agonists for the preparation of healing drugs and to the pharmaceutical compositions for said use.

This application is a 371 of PCT/FR98/00105 filed Jan. 21, 1998.

The present invention relates to a novel indication of β₃-adrenergicreceptor agonists.

More particularly, the invention relates to the use of β₃-adrenergicreceptor agonists for the preparation of wound healing drugs.

It is known that β₃-adrenergic receptor agonists are capable of beingused for the treatment of obesity and diabetes, although the clinicalproof of this activity has not been provided with certainty.

It is also known that β₃-adrenergic receptor agonists, hereafterabbreviated to “β₃-agonists”, have been proposed as intestinalspasmolytics for the treatment of gastrointestinal diseases, moreparticularly inflammatory bowel disease (IBD) and irritable colonsyndrome, and for protection of the gastrointestinal tract from the sideeffects of non-steroidal anti-inflammatory drugs.

The term “β₃-agonists” includes β receptor agonist compounds which havebeen defined as “atypical” or “non-β₁non-β₂” and which are nowrecognized as a subtype of adrenergic receptor called “β₃”.

The treatment of wounds which do not heal represents a serious clinicalproblem that is difficult to solve because the healing of woundsinvolves a complex series of phenomena which overlap and which aredifficult to control globally.

Growth factors, especially basic Fibroblast Growth Factor (bFGF, Biol.Pharm. Bull., 1996, 19(4), 530-535) and acidic Fibroblast Growth Factor(aFGF, J. Invest. Dermatol., 1995, 104, 850-855), as well assphingosylphosphorylcholine, J. Invest. Dermatol., 1996, 106, 232-237,have been proposed as wound healing agents.

It has now been found that β₃-agonists possess a definite activity onthe healing of wounds in mammals.

More particularly, it has been found that β₃-agonists act byaccelerating the healing of skin wounds in diabetic mammals.

Thus, according to one of its features, the present invention relates tothe use of β₃-agonists for the preparation of pharmaceuticalcompositions intended for accelerating the healing of wounds.

More particularly, the invention relates to the use of β₃-agonists forthe preparation of wound healing drugs.

β₃-agonists which are useful according to the present invention arerepresented by formula (I):

in which:

X is hydrogen, a halogen, a trifluoromethyl group or a (C₁-C₄)alkylgroup; and

R is hydrogen or a methyl group which is unsubstituted or substituted bya carboxyl or lower carbalkoxy group, and their pharmaceuticallyacceptable salts, indicated in EP 0 211 721 and EP 0 303 546, whichdescribe compounds of formula (1) which are useful as intestinalspasmolytics.

Among the compounds of formula (I), the following compounds:

2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-phenylethanol;

2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)-ethanol;

2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol;

2-[(7-carbethoxymethoxy-1,2,3,4tetrahydronaphth-2-yl)amino]-1-phenylethanol;

(1R,2′RS)-2-[(7-hydroxy-1,2,3,4tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

(1S,2′RS2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

(+)-(1R)-2-[(7-hydroxy-1,2,3,4tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

(+)-(1S)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

(−)-(1R)2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

(−)-(1S)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenyl-ethanol;

N-[(2R)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-(3-chlorophenyl)-2-hydroxyethanamine;

N-[(2R)-7-methoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-2R)-2-(3-chlorophenyl)-2-bydroxyethanamine;

and especiallyN-[(2S7ethoxycarbonylmethoxy-1,2,3,4tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine(SR 58611),

and their pharmaceutically acceptable salts, are particularlyadvantageous.

Other β₃-agonists which are useful according to the present inventionare represented by formula (II):

in which:

n is 1, 2 or 3;

A is a benzofuran-2-yl group or a phenyl group which is unsubstituted orsubstituted by one or two halogen atoms or by a (C₁-C₄)alkyl ortrifluoromethyl group;

R′ is:

a hydrogen;

a (C₁-C₆)alkyl group;

a functional group selected from the following groups: hydroxyl;(C₁-C₆)alkoxy; (C₂-C₆)alkenyloxy; (C₂-C₆)alkynyloxy; (C₃-C₈)cycloalkoxy;(C₃-C₈)-cycloalkyl(C₁-C₆)alkoxy; benzyloxy; phenoxy, mercapto;(C₁-C₆)alkylthio; (C₂-C₆)alkenylthio; (C₂-C₆)alkynylthio;(C₃-C₈)cycloalkylthio; (C₃-C₈)cycloalkyl-(C₁-C₆)alkylthio; benzylthio;phenylthio; ((C₁-C₆)alkyl)sulfinyl; ((C₂-C₆)alkenyl)-sulfinyl;((C₂-C₆)alkynyl)sulfonyl; (C₃-C₈)cycloalkylsulfonyl; ((C₃-C₈)cycloalkyl)(C₁-C₆)alkyl)sulfonyl; benzylsulfonyl; phenylsulfonyl;((C₁-C₆)alkyl)sulfonyl; ((C₂-C₆)alkenyl)sulfonyl;((C₂-C₆)alkynyl)sulfonyl; (C₃-C₈)cycloalkylsulfonyl;((C₃-C₈)cycloalkyl(C₁-C₆)alkyl)sulfonyl; benzylsulfonyl; phenylsulfonyl;cyano; nitro; amino which is unsubstituted or substituted by one or twoidentical or different radicals selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl, phenyl; carboxyl; carbalkoxy inwhich the alkyl group is C₁-C₆; ((C₂-C₆)alkenyloxy)carbonyl;((C₂-C₆)alkynyloxy)carbonyl; (C₃-C₈)cycloalkylcarbonyl;((C₃-C₈)cycloalkyl(C₁-C₆)alkoxy)carbonyl; benzyloxycarbonyl;phenoxycarbonyl; carbamoyl which is unsubstituted or substituted on theamino group by one or two identical or different radicals selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenyl groups;

a group R′″ selected from the groups: (C₁-C₆)alkyl substituted by afunctional group; (C₂-C₆)alkenyl substituted by a functional group;(C₂-C₆)alkynyl substituted by a functional group; phenyl(C₁-C₆)alkylsubstituted on the phenyl group by a (C₁-C₆)alkyl or by a functionalgroup; phenyl(C₂-C₆)alkenyl substituted on the phenyl group by a(C₁-C₆)alkyl or by a functional group; phenyl(C₂-C₆)alkynyl substitutedon the phenyl group by a (C₁-C₆)alkyl or by a functional group; benzylsubstituted on the phenyl group by a (C₁-C₆)alkyl or by a functionalgroup; and phenyl which is unsubstituted or substituted by a(C₁-C₆)alkyl or by a functional group, the functional group being asdefined above;

a group O-R′″, S-R′″, SO-R′″ or SO₂—R′″, in which R′″ is as definedabove for R′;

a group NR′″R°, in which R′″ is as defined above and R′ is hydrogen oris as defined above for R′″, or R′″ and R° form, together with thenitrogen to which they are bonded, a group selected from pyrrolidino,piperidino and morpholino groups;

a group COOR′″ or a group CO-SR′″, in which R′″ is as defined above;

a group CONR′″R°, in which R′″ is as defined above and R° is hydrogen oris as defined above for R′″, or R′″ and R° form, together with thenitrogen to which they are bonded, a group selected from pyrrolidino,piperidino and morpholino groups; or

a group SO₂NR′″R°, in which R′″ is as defined above and R° is hydrogenor is as defined above for R′″, or R′″ and R° form, together with thenitrogen to which they are bonded, a group selected from pyrrolidino,piperidino and morpholino groups;

R″ is:

a hydrogen;

a halogen;

a (C₁-C₆)alkyl group;

a functional group as defined above for R′;

a group OR′″, R′″ being as defined above;

a group COOR′″, R′″ being as defined above;

a group CONR′″R°, in which R′″ is as defined above and R° is hydrogen oris as defined above for R′″, or R′″ and R° form together with thenitrogen to which they are bonded, a group selected from pyrrolidino,piperidino and morpholino groups;

W is a direct bond or an oxygen atom;

X′ is hydrogen, a (C₁-C₆)alkyl or a (C₁-C₆)alkycarbonyl;

Y is hydrogen or a group A′—CH(OH)—CH₂—, A′ being identical to A butother than benzofuran-2-yl; or

X′ and Y, taken together, form a methylene group optionally substitutedby a carbalkoxy group in which the alkyl group is C₁-C₆; an ethylenegroup optionally substituted by an oxo group; or a 1,3-propylene group;

Z is hydrogen or a (C₁-C₆)alkyl,

and their pharmaceutically acceptable salts, indicated in EP 0 255 415,which describes the use of compounds of formula (II) as intestinalspasmolytics.

Other β₃-agonists which are also useful according to the presentinvention are represented by formula (III):

in which:

E is hydrogen, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy group, a phenylgroup, a nitro group, a halogen atom or a trifluoromethyl group;

L is hydrogen, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy group, a phenylgroup, a nitro group or a halogen atom; or

E and L together are a group —CH═CH—CH—CH— or —CH₂—CH₂—CH₂—CH₂—; and

G is hydrogen, a chlorine atom, a hydroxyl group or a group OG′, inwhich G′ is a (C₁-C₄)alkyl group which is unsubstituted or substitutedby a hydroxyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, carboxyl or(C₃-C₇)cycloalkyl group; a (C₃-C₇) cycloalkyl group; or a(C₂-C₄)alkanoyl group,

and their pharmaceutically acceptable salts, indicated in EP 0436435,which describes compounds of formula (o) that are useful as intestinalspasmolytics.

Among the compounds of formula (III),N-[(6hydroxy-1,2,3,4-tetrahydro-naphthalen-(2R)-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine(SR 59104),N-[(7-methoxy-1,2,3,4-tetrabydonaphthalen-(2R)-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine(SR 59119) and their pharmaceutically acceptable salts are particularlyadvantageous compounds.

Other advantageous β₃-agonist compounds according to the presentinvention are:

the compound BRL 35135 described in EP 23385, of the formula

the compound CL 316243 described in U.S. Pat. No. 5,061,727, of theformula

the compound AZ 002 described in EP 218440, of the formula

the compound BMS 187257 described in U.S. Pat. No. 5,321,036, of theformula

the compound L-755507 of the formula

and the compound L-750355 of the formula

which are described in EP 611003;

the compound FR-149175 described in Japan J. Pharmacol., 1997, 74. (1):109, of the formula

the compound SB-226552 described in Int. J. Obesity, 1997, 21, Suppl. 2:560, of the formula

and the products described in the following patents/patent applications:WO 96/35671, WO 96/35670, WO 96/16038, WO 96104233, WO 95/33724, WO95/29159, EP 659737, WO 95/04047, EP 516349, EP 473285, EP 23385,EP21636, EP 7205, JP08198866, JP08165276, JP08157470, WO96116938, EP714883, WO 96/04234, U.S. Pat. No. 5,488,064, U.S. Pat. No. 5,482,971,U.S. Pat. No. 5,491,134, WO 95/29159, WO 95133724, ZA 9409874, WO95/29903, U.S. Pat. No. 5,461,163, WO 95125104, EP 659737, JP 07112958,WO 9518527, WO 95/07284, JP 07025756, WO 95/03289, WO 95104047, WO95/01170, WO 94/29290, U.S. Pat. No. 5,373,020, JP 06293664, WO94/12166, EP 611003, WO 97/10825, WO 97121666, WO 97/21665, 3P 09118655,WO 97/15549, GB 2305665, EP 764640, EP 764632, WO 97/10822.

The activity of the compounds was demonstrated by means of a test formeasuring the healing after a 1 cm² skin lesion had been created on theback of a mouse by removing a fragment of skin. Diabetic animals weresubjected to a study of β₃-agonist versus placebo. The compound wasadministered orally at a rate of 10 mg/kg. The healing was evaluated bydaily measurement of the surface area of the lesion in the treatedanimals and in those receiving the placebo.

The results of this study showed a clear difference in healing betweenthe animals treated with the β₃-agonist compound and the animalsreceiving the placebo, namely that the lesions heal much more quicklyfor the treated animals than for those receiving the placebo.

By virtue of this particular healing activity and their low toxicity,enabling them to be used as drugs, the β₃-agonist compounds candefinitely be employed in the prophylaxis and/or treatment of skinwounds, especially in the prophylaxis and/or treatment of wounds in thelower limbs of diabetic mammals.

Thus, according to another of its features, the present inventionrelates to a method for the prophylaxis and/or treatment of wounds inmammals, said method being characterized in that a prophylactic and/oreffective amount of a β₃-agonist compound is administered to saidmammals requiring said prophylaxis and/or said treatment.

More particularly, according to one preferred feature, the presentinvention relates to a method for the prophylaxis and/or treatment ofwounds in mammals, said method being characterized in that aprophylactic and/or effective amount of a compound selected from thecompounds of formulae (I), (II) and (III) is administered to saidmammals requiring said prophylaxis and/or said treatment.

The amount of active principle to be administered in the treatment ofwounds according to the present invention depends on the nature andseverity of the complaints to be treated and on the potency of thecompound and the patient's weight. The dose is generally between 0.01and 30 mg per kg of body weight, preferably between 0.1 and 20 mg per kgof body weight and especially between 1 and 10 mg per kg of body weight.

This dose can optionally be subdivided into 2, 3 or 4 administrationsthroughout the day. Preferably, the active principle is formulated indosage units containing from 0.1 to 400 mg and preferably from 0.5 to200 mg of active principle, in combination with a pharmaceuticalcarrier.

In the case of local treatment, which can complement systemicadministration, the dosage unit depends on the severity and extent ofthe wounds and on the concentration of active principle in thepharmaceutical formulation.

The normal practice is to use a cream, an ointment or a gel containingfrom 0.01 to 5%, advantageously from 0.025 to 2.5% and preferably from0.1 to 1% of β₃-agonist, mixed with the customary excipients for topicalapplication.

It is also possible to use a lotion or, in general, a solution orsuspension in which the β3-agonist is present at concentrations of0.0001 to 1%.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal,rectal or local administration, the active principles can beadministered to animals and humans in unit forms of administration,either as such, for example in lyophilized form, or mixed withconventional pharmaceutical carriers, for the treatment of theabove-mentioned complaints. The appropriate unit forms of administrationinclude oral forms such as tablets, which may be divisible, gelatincapsules, powders, granules and solutions or suspensions to be takenorally, sublingual and buccal forms of administration, subcutaneous,intramuscular or intravenous forms of administration, local forms ofadministration and rectal forms of administration.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talcum, gum arabic or thelike. The tablets can be coated with sucrose or other appropriatesubstances, or else they can be treated so as to have a prolonged ordelayed activity and so as to release a predetermined amount of activeprinciple continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and pouring the resulting mixture intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the activeingredient together with a sweetener, which is preferably calorie-free,methyl-paraben and propylparaben as antiseptics, a flavoring and anappropriate color.

The water-dispersible powders or granules can contain the activeingredient mixed with dispersants, wetting agents or suspending agents,such as polyvinyl-pyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, salinesolutions or injectable sterile solutions containing pharmacologicallycompatible dispersants and/or wetting agents, for example propyleneglycol or butylene glycol.

The active principle can also be formulated as microcapsules, optionallywith one or more carriers or additives.

For local administration, the active principle is mixed with anexcipient for the preparation of lotions, gels, creams or unguents, orit is dissolved in an appropriate vehicle.

In the pharmaceutical compositions according to the present invention,the active principle can also be in the form of an inclusion complex incyclodextrins, their ethers or their esters.

What is claimed is:
 1. A method for accelerating the healing of woundsin mammals comprising administering to said mammals a wound-healingaccelerating amount of a β₃-agonist.
 2. A method according to claim 1for accelerating the healing of wounds in the lower limbs of diabeticmammals.
 3. A method according to claim 1 wherein the β3-agonist is acompound of formula (1):

in which: X is hydrogen, a halogen, a trifluoromethyl group or a(C₁-C₄)alkyl group; and R is hydrogen or a methyl group which isunsubstituted or substituted by a carboxyl or lower carbalkoxy group, orone of its pharmaceutically acceptable salts.
 4. A method according toclaim 3, wherein the β₃-agonist isN-[(2R)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamineor one of its pharmaceutically acceptable salts.
 5. A method accordingto claim 1 wherein the β₃-agonist is a compound of formula (II):

in which: n is 1, 2 or 3; A is a benzofuran-2-yl group or a phenyl groupwhich is unsubstituted or substituted by one or two halogen atoms or bya (C₁-C₄)alkyl or trifluoromethyl group; R′ is: a hydrogen; a(C₁-C₆)alkyl group; a functional group selected from the followinggroups: hydroxyl; (C₁-C₆)-alkoxy; (C₂-C₆)alkenyloxy; (C₂-C₆)alkynyloxy;(C₃-C₈)cycloalkoxy; (C₃-C₈)-cycloalkyl(C₁-C₆)alkoxy; benzyloxy, phenoxy;mercapto; (C₁-C₆)alkylthio; (C₂-C₆)alkenylthio; (C₂-C₆)alkynylthio;(C₃-C₈)cycloalkylthio; (C₃-C₈)cycloalkyl(C₁-C₆)alkylthio; benzylthio;phenylthio; ((C₁-C₆)alkyl)sulfinyl; ((C₂-C₆)alkenyl)sulfinyl;((C₂-C₆)alkynyl)sulfinyl; (C₃-C₈)cycloalkylsulfonyl;((C₃-C₈)cycloalkyl(C₁-C₆)alkyl)sulfinyl; benzylsulfonyl; phenylsulfonyl;((C₁-C₆)alkyl)sulfonyl; ((C₂-C₆)-alkenyl)sulfonyl;((C₂-C₆)alkynyl)sulfonyl; (C₃-C₈)cycloalkylsulfonyl;((C₃-C₈)-cycloalkyl(C₁-C₆)alkyl)sulfonyl; benzylsulfonyl;phenylsulfonyl; cyano; nitro; amino which is unsubstituted orsubstituted by one or two identical or different radicals selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl, phenyl; carboxyl; carbalkoxy inwhich the alkyl group is C₁-C₆; ((C₂-C₆)alkenyloxy)carbonyl;((C₂-C₆)alkynyloxy)carbonyl; (C₃-C₈)cycloalkoxycarbonyl;((C₃-C₈)cycloalkyl(C₁-C₆)alkoxy)carbonyl; benzyloxy-carbonyl;phenoxycarbonyl; carbamoyl which is unsubstituted or substituted on theamino group by one or two identical or different radicals selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, benzyl and phenyl groups; a group R″′selected from the groups: (C₁-C₆)alkyl substituted by a functionalgroup; (C₂-C₆)alkenyl substituted by a functional group; (C₂-C₆)alkynylsubstituted by a functional group; phenyl(C₁-C₆)alkyl substituted on thephenyl group by a (C₁-C₆)alkyl or by a functional group;phenyl(C₂-C₆)alkenyl substituted on the phenyl group by a (C₁-C₆)alkylor by a functional group; phenyl(C₂-C₆)alkynyl substituted on the phenylgroup by a (C₁-C₆)alkyl or by a functional group; benzyl substituted bya (C₁-C₆)alkyl or by a functional group; and phenyl which isunsubstituted or substituted by a (C₁-C₆)alkyl or by a functional group,the functional group being as defined above for R′; a group O-R′″,S-R′″, SO-R′″ or SO₂R′″, in which R′″ is as defined above; a groupNR′″R°, in which R′″ is as defined above and R° is hydrogen or is asdefined above for R′″, or R′″ and R° form, together with the nitrogen towhich they are bonded, a group selected from pyrrolidino, piperidino andmorpholino groups; a group COOR′″ or a group COSR′″, in which R′″ is asdefined above; a group CONR′″R°, in which R′″ is as defined above and R°is hydrogen or is as defined above for R′″, or R′″ and R° form, togetherwith the nitrogen to which they are bonded, a group selected frompyrrolidino, piperidino and morpholino groups; or a group SO₂NR′″R°, inwhich R′″ is as defined above and R° is hydrogen or is as defined abovefor R′″, or R′″ and R° form, together with the nitrogen to which theyare bonded, a group selected from pyrrolidino, piperidino and morpholinogroups; R″ is: a hydrogen; a halogen; a (C₁-C₆)alkyl group; a functionalgroup as defined above for R′; a group OR′″, R′″ being as defined above;a group COR′″, R′″ being as defined above; or a group CONR′″R°, in whichR′″ is as defined above and R° is hydrogen or is as defined above forR′″, or R′″ and R° form, together with the nitrogen to which they arebonded, a group selected from pyrrolidino, piperidino and morpholinogroups; W is a direct bond or an oxygen atom; X′ is hydrogen, a(C₁-C₆)alkyl or a (C₁-C₆)alkylcarbonyl; Y is hydrogen or a groupA′—CH(OH)CH₂—, A′ being identical to A but other than benzofuran-2-yl;or X′ and Y, taken together, form a methylene group optionallysubstituted by a carbalkoxy group in which the alkyl group is C₁-C₆; anethylene group optionally substituted by an oxo group; or a1,3-propylene group; Z is hydrogen or a (C₁-C₆)alkyl, or one of itspharmaceutically acceptable salts.
 6. A method according to claim 1wherein the β₃-agonist is a compound of formula (III):

in which: E is hydrogen, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy group, aphenyl group, a nitro group, a halogen atom or a trifluoromethyl group;L is hydrogen, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy group, a phenylgroup, a nitro group or a halogen atom; or E and L together are a group—CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—; and G is hydrogen, a chlorine atom,a hydroxyl group or a group OG′, in which G′ is a (C₁-C₄)alkyl groupwhich is unsubstituted or substituted by a hydroxyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, carboxyl or (C₃-C₇)cycloalkyl group; a(C₃-C₇)cycloalkyl group; or a (C₂-C)alkanoyl group, or one of itspharmaceutically acceptable salts.
 7. A method according to claim 6,wherein the β₃-agonist is selected fromN-[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-(2R)-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine,N-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-(2R2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamineand their pharmaceutically acceptable salts.
 8. A method for theprophylaxis or treatment of wounds in mammals which comprisesadministering to mammals in need of such treatment an effective amountof a β₃-agonist.